Substituted 2,3-dihydro-1H-inden-1-one Retinoic acid-related orphan nuclear receptor Antagonists for Treating Multiple Sclerosis

Abstract

The present invention is directed to compounds, their synthesis, and their use as antagonists, inverse agonists, modulators and or inhibitors of the Retinoic acid-related orphan nuclear receptor γt (RORγt) / RORγ. The compounds of the present invention are useful for modulating RORγt) / RORγ activity and for treating diseases or conditions mediated by RORγt) / RORγ such as for example, disease states associated with immunopathology of human autoimmune diseases such as Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Inflammatory Colitis, Psoriasis, COPD, Pain, Obesity, Diabetes, Dyslipidemia, Osteoporosis, Asthma, Neurodegenerative diseases and Cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Patent Application 61 / 876,099 filed Sep. 10, 2013, the entirety of which is incorporated herein by reference.FIELD OF INVENTION[0002]The present invention is directed to compounds, their synthesis, and their use as antagonists, inverse agonists, modulators and or inhibitors of the Retinoic acid-related Orphan nuclear Receptor γt (RORγt) / RORγ. In particular, the present invention is directed to substituted 2,3-dihydro-1H-inden-1-one compounds that modulate (RORγt) / RORγ. The compounds of the present invention are useful for modulating (RORγt) / RORγ activity and for treating diseases or conditions mediated by (RORγt) / RORγ such as, for example, disease states associated with immunopathology of human autoimmune diseases such as Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Inflammatory Colitis, Psoriasis, Chronic Obstructive Pulmonary Disease (COPD), Pain, Obesity, Diabetes, Dyslipidemia, Osteop...

AI Technical Summary

Benefits of technology

This patent is about new compounds that can treat diseases caused by a special protein called ROR submitted by the inventor. The compounds can inhibit or modulate ROR and are particularly effective at treating autoimmune diseases like multiple sclerosis, rheumatoid arthritis, inflammatory colitis, and others. The patent also describes the methods for making and using these compounds.

Problems solved by technology

MS substantially and adversely affects the quality of life of each individual, with symptoms that include loss of muscle control and strength, fatigue, weakness, loss of vision, spasticity, balance, sensation, bladder and bowel problems, numbness, vision loss, tremors, and adverse mental function such as depression.

In the United States alone MS care is estimated to cost nearly $13 billion per year.

It includes relapsing-remitting MS (RRMS) drugs such as Immunomodulatory (β-interferons) therapeutics (Avonex, Betaseron, Rebif and Extavia), Monoclonal Antibodies (Tysabri, Lemtrada), other immunosuppressants (Mitoxantrone), Copaxone (glatiramer acetate injection) and oral agents; Teriflunomide, Fingolimod but none of these medications is a cure or prevent recurring symptoms.

In addition to existing oral DMDs such as Fingolimod, and recently approved Tecfidera (BG-12 or Dimethyl Fumarate) and other experimental agents yet to be approved are in Phase III of clinical development such as Laquinimod, and Masitinib (oral immunomodulators) have been reported to cause opportunistic infections, antibody stimulation, liver and kidney toxicities.

Presently, oral DMT drugs such as Fingolimod, Cladribine, and Tecfidera—as well as about 46 other experimental agents in various stages of clinical development such as Laquinimode, and Masitinib—have been reported to cause serious adverse events including opportunistic infections, antibody stimulation, and liver and kidney toxicities.

Many of these approved and experimental agents yet to be approved create serious adverse events including opportunistic infections, antibody stimulation, and liver and kidney toxicities.

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